Schizophrenia is a devastating psychiatric condition that affects approximately 0.4-1% of the US population. Substantial convergent evidence from drug studies, therapeutic treatments, and human imaging studies demonstrate that psychosis in schizophrenia is associated with a dysregulation of subcortical dopamine system function. This dopamine hypothesis of schizophrenia has one major caveat in that there appears to be no specific pathology in the midbrain dopamine system itself. Thus it is likely that it is the afferent regulation of the dopamine system that is dysfunctional in schizophrenia. Two such inputs are the medial prefrontal cortex (thought to be largely associated with cognitive deficits) and the hippocampus, a temporal lobe structure principally associated with learning and memory. Alterations in hippocampal structure and function in schizophrenia are consistently demonstrated in postmortem and neuro-imaging studies. Furthermore, there is increasing evidence for baseline hippocampal hyperactivity in human schizophrenia patients that is correlated with levels of psychosis. Consistent with this, we have recently reported baseline hyperactivity in the ventral hippocampus in a developmental disruption rodent model, namely MAM G17, that appears to be the driving force behind the dopamine hyperfunction in this model. Thus, attenuation of ventral hippocampal output may act to normalize dopamine transmission and may provide a novel therapeutic target. We plan to examine this model utilizing distinct approaches aimed specifically at modulating ventral hippocampal activity along the following Specific Aims: 1) Examine potential novel methods for regulating vHipp function in MAM and saline rats, 2) Determine how these methods for attenuating vHipp activity alter dopamine system function in MAM and saline rats, and 3) Determine whether attenuating vHipp system function can reverse behavioral deficits associated with schizophrenia in the MAM model. Examining the functional interactions among these systems and how disruption within this circuit affects information processing, neurochemistry and behavior is central to our ultimate goal of identifying new and improved therapeutic agents.

Public Health Relevance

Schizophrenia is a devastating psychiatric condition that affects 0.4% of the US population. One brain region commonly associated with this disease is the hippocampus. In this project we will examine novel methods for altering activity in this brain region in an attempt to better understand disease pathophysiology, with the ultimate goal being the development of improved therapeutic agents.

National Institute of Health (NIH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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University of Texas Health Science Center
Schools of Medicine
San Antonio
United States
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Perez, Stephanie M; Carreno, Flavia R; Frazer, Alan et al. (2014) Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia. J Neurosci 34:9261-7
Boley, Angela M; Perez, Stephanie M; Lodge, Daniel J (2014) A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia. Schizophr Res 157:238-43
Chen, Li; Perez, Stephanie M; Lodge, Daniel J (2014) An augmented dopamine system function is present prior to puberty in the methylazoxymethanol acetate rodent model of schizophrenia. Dev Neurobiol 74:907-17
Perez, Stephanie M; Chen, Li; Lodge, Daniel J (2014) Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia. Psychoneuroendocrinology 47:88-97
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Perez, S M; Lodge, D J (2013) Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia. Mol Psychiatry 18:1193-8
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Shah, A; Lodge, D J (2013) A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia. Transl Psychiatry 3:e215
Lodge, Daniel J (2011) The medial prefrontal and orbitofrontal cortices differentially regulate dopamine system function. Neuropsychopharmacology 36:1227-36
Gill, Kathryn M; Lodge, Daniel J; Cook, James M et al. (2011) A novel ?5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia. Neuropsychopharmacology 36:1903-11